This phase II trial studies the effect of P140K MGMT hematopoietic stem cells, O6-benzylguanine, temozolomide, and carmustine in treating participants with supratentorial glioblastoma or gliosarcoma who have recently had surgery to remove most or all of the brain tumor (resected). Chemotherapy drugs, such as 6-benzylguanine, temozolomide, and carmustine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing. Placing P140K MGMT, a gene that has been created in the laboratory into bone marrow making the bone more resistant to chemotherapy, allowing intra-patient dose escalation which kills more tumor cells while allowing bone marrow to survive.
Patients with histologically confirmed, newly diagnosed, supratentorial glioblastoma or gliosarcoma who have undergone gross total tumor resection or near gross total resection (resection of >85% of enhancing tumor demonstrated by MRI) are eligible up to 35 days post-operatively. Patients with primarily infratentorial disease, or with multifocal,or leptomeningeal dissemination of disease will be excluded. In general, patients will not have > 1 cm residual measurable or evaluable disease after surgical tumor resection.
Patient must have unmethylated MGMT
Absence Of IDH1 or IDH2mutation on tumor tissue by a CLIA-approved immunohistochemistry or DNA sequencing test on local testing
Patients aged 18-75 years.
Any known medical or hereditary condition associated with immunosuppression;orothermedical illness which may jeopardize patient safety.
Known history of HIV seropositivity. This exclusion is included for two reasons. First, there is evidence of decreased marrow reserve in HIV+ patients and antiviral treatment is associated with myelosuppression. Thus, drug treatment designed to be myelosuppressive may bemore toxic in this patient population. Second, extensive laboratory culturing of the bone marrow and peripheral blood progenitor cells is required. No preclinical samples which are HIV+ have been evaluated with the gene transfer modality proposed and thus the feasibility and safety of gene transfer and selection in HIV+ samples cannot yet be advocated. Such studies are planned so as to not preclude HIV+ patients in later studies.
Pregnant or lactating women. There is data to indicate that BCNU and TMZ is teratogenic and carcinogenic. Thus, its use in pregnant women would confer unnecessary risk to the fetus.
Patients with symptomatic pulmonary disease and other severe co-morbid respiratory conditions, including patients with active pulmonary infection and/or pulse oximetry < 90% and a corrected DLCO < 50% of predicted. However, subjects with a corrected DLCO in the range of 50-70% should have Pulmonologyclearance prior to intervention.
Single group
P140K-MGMT
Biological/VaccineEx Vivo Cultured P140K MGMT CD34+ Cells. The transduced cells are a biological product and production is detailed in the Cellular Therapy Lab standard operating procedures and IND 14099
O6-benzylguanine
DrugO6BG is a low molecular-weight purine analog which selectively and irreversibly inactivates the DNA-repair enzyme, O6- alkylguanine DNA-alkyltransferase.
Photon Based Radiotherapy
RadiationStandard of care, photon-based radiotherapy (60Gy in 30 fractions) will be performed in both arms without concomitant TMZ between to 6 weeks post-operatively. Radiotherapy will be performed at UH-SCC.
temozolomide
DrugTemozolomide is not directly active but undergoes rapid non-enzymatic conversion at physiologic pHto the reactive compoundMTIC. The cytotoxicity of MTIC is thought to be primarily due to alkylationof DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine
Filgrastim
DrugFilgrastim is a 175 amino acid protein manufactured by recombinant DNA technology. Endogenous filgrastim is a glycoprotein produced by monocytes, fibroblasts, and endothelial cells, which regulates the production of neutrophils within the bone marrow.
carmustine
DrugBCNU is a lipid soluble agent which has alkylating properties, plus an isocyanate metabolite which interferes with DNA and RNA synthesis.
Percent of participants able to complete treatment
To evaluate and compare the feasibility of introducing and expressing P140K MGMT cDNA using a lentiviral-based provirus in autologous hematopoietic stem cells harvested from newly diagnosed IDH-1 WT GBM with unmethylated MGMT promoter using two different sequences of stem cell mobilization. 1\. What percent of patients who enter trial can complete treatment.
Incidence of adverse events
proportion of participants experiencing a grade 3 or higher AE/SAE
Overall Survival
Median overall survival in months.
Myelosuppression
To determine what proportion of patients who receive P140K MGMT transduced CD34 cells tolerate BG and dose escalated TMZ without myelosuppression. We will report % of patients who suffer grade I-5 SAES related to myelosuppression.
Detection of P140K transduced BG and TMZ resistant cells
% of patients with detectable P-140K-MGMT
Enrichment of P140K-MGMT
What % of patients have enrichment of P140K-MGMT.
Tumor Response using imaging
Tumor response assessed via iRANO criteria
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Leland Metheny
Lead sponsor
Case Comprehensive Cancer Center
Sponsor institution
National Cancer Institute (NCI)
Collaborator
